The specific metabolic events which give rise to the appearance of hunger have not yet been specified. Traditional theories hold that hunger appears because glucose utilization is decreased, or because bodily fat reserves are depleted. Alternatively, it is possible to integrate these two views by assuming that hunger occurs whenever the supply of oxidizable metabolic fuels is reduced below some critical level. This approach focuses on the availability of all metabolic fuels, not just glucose, and emphasizes the changes in the fuel supply that can result from variations in lipogenesis and lipolysis. Thus, the goal of the proposed research is to gather more information on the metabolic origins of hunger by examining to what extent changes in the supply of metabolic fuels affect feeding behavior in rats. The availability of metabolic fuels will be experimentally varied through diet modifications, and by hormonal manipulations of fuel storage and mobilization. Blood concentrations of the major metabolic fuels (i.e. glucose, free fatty acids, and ketone bodies) will be measured in order to verify that experimental manipulations produced the desired metabolic effects, and to quantify the relationship between fuel availability and food consumption. To gain further control over the fuel supply, rats with experimental diabetes mellitus will be used (in addition to normal rats) because diabetic rats are limited to fat as their primary source of oxidizable fuels. Finally, the effect of ventromedial hypothalamic lesions on feeding, obesity, fuel availability, and in vivo lipogenesis in normal and diabetic rats will be studied to determine to what extent changes in energy metabolism are responsible for hyperphagia following such brain damage.